Genital infection with Chlamydia trachomatis remains the most prevalent bacterial sexually transmitted disease, resulting in significant morbidity in the female in the form of pelvic inflammatory disease, involuntary infertility, and ectopic pregnancy. Consequently, the major research emphasis has been directed toward the understanding of the disease processes and protective immune response in the female with the ultimate goal of developing a vaccine to protect against upper genital tract disease. However, a vaccine would also be used to protect males against disease. Immunizing males would have the obvious advantage of reducing the infectious dose for females and thereby enhance the protective capabilities of the vaccine in the female. Other than epidemiological or diagnostic studies, there have been only a handful of reports addressing the host response to chlamydial infections in the male, and virtually nothing is known about the local immune response in the male genital tract to any sexually transmitted agent. Other than primates, the only animal model in which the course of infection in males following urethral inoculation has been studied is the guinea pig infected with the Chlamydia psittaci agent of guinea pig inclusion conjunctivitis (GPIC), a natural parasite of the guinea pig. Of major interest was our observation that the majority of male guinea pigs recovered from a primary GPIC infection were completely immune to reinfection for long periods of time, whereas female guinea pigs were 100% susceptible to reinfection over the same time frame, suggesting that there is some aspect of the immune response in males which provides a better protective response. We have also demonstrated that sexual transmission from males to females can be accomplished reliably in a predictable time period. Of major importance was our observation that the females infected by sexual transmission shed chlamydiae for a significantly shorter period of time than any animal infected artificially with a comparable dose. This suggested that factors in semen may enhance the host response in the female genital tract. Therefore, the major objective of this proposal is to explore the innate and adaptive immune responses in the male urethra and to test the hypothesis that factors in semen may affect the course of the infection in the female. The Specific Aims will be 1) to characterize the immune response in the male urethra in guinea pigs to a primary GPIC infection and to reinfection, 2) to determine the basis for long-term sterile immunity following a primary infection in contrast to partial immunity resulting from artificial immunization, and 3) to determine the mechanism of abbreviated infection in female guinea pigs infected with GPIC by sexual transmission.